Tang Lu, Chen Lu, Liu Xiaolu, He Ji, Ma Yan, Zhang Nan, Fan Dongsheng
Department of Neurology, Peking University Third Hospital, Beijing, China.
Beijing Key Laboratory of Biomarker and Translational Research in Neurodegenerative Diseases, Peking University Third Hospital, Beijing, China.
Front Neurol. 2022 Aug 3;13:939775. doi: 10.3389/fneur.2022.939775. eCollection 2022.
To explore whether the repeat lengths of the chromosome 9 open reading frame 72 () gene and the ataxin-2 () gene in amyotrophic lateral sclerosis (ALS) patients without repeat expansions confer a risk of ALS or survival disadvantages in ALS.
We screened a hospital-based cohort of Chinese patients with sporadic ALS without repeat expansions and neurologically healthy controls for GGGGCC and CAG repeat length to compare the frequency of possible detrimental length alleles using several thresholds. Furthermore, the clinical features of ALS were compared between patients with ALS subgroups using different length thresholds of maximum and repeat alleles, such as sex, age of onset, diagnostic delay, and survival.
Overall, 879 sporadic patients with ALS and 535 controls were included and the repeat lengths of the and were both detected. We found significant survival differences in patients using a series of repeat length thresholds from 2 to 5, among which the most significant difference was at the cutoff value of 2 (repeats 2 vs. >2: median survival 67 vs. 55 months, log-rank = 0.032). Furthermore, Cox regression analysis revealed the role of age of onset [hazard ratio (HR) 1.04, 95% CI 1.03-1.05, < 0.001], diagnostic delay (0.95, 0.94-0.96, < 0.001), and carrying repeat length of 2 (0.72, 0.59-0.89, = 0.002) in the survival of patients without repeat expansions. In addition, bulbar onset was associated with poorer survival when the patients carried the maximum repeat allele over 2 (1.81, 1.32-2.48, < 0.001). However, no survival difference was found when applying a series of continuous cutoff values of or stratified by repeats of 2.
The length of 2 in the maximum repeat allele was identified to be associated with favorable survival in ALS patients without repeat expansions. Our findings from the clinical setting implicated the possible cutoff definition of detrimental C9orf72 repeats, which should be helpful in the understanding of genetics in ALS and in clinical genetic counseling.
探讨在无 C9orf72 重复序列扩增的肌萎缩侧索硬化症（ALS）患者中，9 号染色体开放阅读框 72（C9orf72）基因和共济失调蛋白 2（ATXN2）基因的重复长度是否会增加患 ALS 的风险或导致 ALS 患者生存劣势。
我们在一个以医院为基础的中国散发性 ALS 患者队列（无 C9orf72 重复序列扩增）和神经功能正常的对照人群中筛查 C9orf72 的 GGGGCC 和 ATXN2 的 CAG 重复长度，使用多个阈值比较可能有害长度等位基因的频率。此外，使用不同长度阈值（如最大 C9orf72 和 ATXN2 重复等位基因）将 ALS 患者分为亚组，比较各亚组患者的 ALS 临床特征，包括性别、发病年龄、诊断延迟和生存情况。
总体而言，纳入了 879 例散发性 ALS 患者和 535 例对照，同时检测了 C9orf72 和 ATXN2 的重复长度。我们发现，使用一系列从 2 到 5 的 C9orf72 重复长度阈值时，患者的生存存在显著差异，其中最显著的差异出现在阈值为 2 时（重复次数为 2 与>2：中位生存期分别为 67 个月和 55 个月，对数秩检验 P = 0.032）。此外，Cox 回归分析显示，发病年龄[风险比（HR）1.04，95%可信区间 1.03 - 1.05，P < 0.001]、诊断延迟（0.95，0.94 - 0.96，P < 0.001）以及携带 C9orf72 重复长度为 2（0.72，0.59 - 0.89，P = 0.002）对无 C9orf72 重复序列扩增患者的生存有影响。此外，当患者携带的最大 ATXN2 重复等位基因超过 2 时，延髓起病与较差的生存相关（1.81，1.32 - 2.48，P < 0.001）。然而，应用一系列连续的 ATXN2 阈值或按 C9orf72 重复次数为 2 进行分层时，未发现生存差异。
在无 C9orf72 重复序列扩增的 ALS 患者中，最大 C9orf72 重复等位基因长度为 2 与较好的生存相关。我们从临床研究中得到的结果暗示了有害 C9orf72 重复序列可能的截断定义，这将有助于理解 ALS 的遗传学机制及临床遗传咨询。
